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A kind of preparation method of prilocaine hydrochloride

A technology for prilocaine hydrochloride and o-toluidine, which is applied in the field of preparation of prilocaine hydrochloride, can solve the problems of flammable solvent, reduced product yield, and complicated operation, and achieves shortening reaction time, lowering production cost, and reducing tediousness. effect of operation

Active Publication Date: 2016-05-04
山东诚汇双达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] (1) In the process of preparing prilocaine hydrochloride, potassium carbonate is used as a catalyst in the reaction and does not participate in the reaction. Potassium carbonate itself is insoluble in acetone. In the post-treatment of the reaction solution, a large amount of water is needed to dissolve and remove potassium carbonate, which increases the The generation of waste liquid pollutes the environment;
[0009] (2) In the reaction process of preparing prilocaine hydrochloride, acetone is used as the reaction solvent. Long-term use of acetone is relatively harmful to the body. Long-term exposure to this product may cause dizziness, burning sensation, pharyngitis, bronchitis, fatigue, irritability, etc.; Long-term repeated skin contact can cause dermatitis
[0010] (3) In the reaction process of preparing prilocaine hydrochloride, acetone is used as the reaction solvent, which is flammable and has certain potential safety hazards
[0011] (4) During the reaction process of preparing prilocaine hydrochloride, the reflux reaction is 20h, the reflux time is relatively long, and by-products are formed at the same time, which reduces the yield of the product
[0012] (5) During the reaction process of preparing prilocaine hydrochloride, after the reaction solution is completely reacted, the acetone solvent in the reaction needs to be concentrated, which also increases energy consumption
[0013] (6) During the reaction process of preparing prilocaine hydrochloride, after the reaction solution is concentrated, it needs to be washed 3 times with water, which will generate a large amount of waste water and bring relatively large environmental protection pressure
[0014] (7) In the reaction process of preparing prilocaine hydrochloride, ethyl acetate needs to be added to extract the product, which increases the cost of the product
[0015] In a word, in the reaction process of preparing prilocaine hydrochloride, the operation is more loaded down with trivial details, is unfavorable for industrialized large-scale production

Method used

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  • A kind of preparation method of prilocaine hydrochloride
  • A kind of preparation method of prilocaine hydrochloride
  • A kind of preparation method of prilocaine hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0043] (a) Add 107g o-toluidine in 600g methylene chloride, stir at room temperature in a 1000ml reaction flask, the rotating speed is 80 revolutions per minute, drop 139g α-chloropropionyl chloride under room temperature, the rate of addition is 4.5 per minute g, the dropping time is 30min. After dropping α-chloropropionyl chloride, the reaction solution is incubated at 20°C for 2.5h. After the incubation is completed, the reaction solution is washed with 4% hydrochloric acid, and the upper layer is discarded. Wash with 3.5% aqueous sodium carbonate solution, discard the upper layer, add 240% water to the organic layer, stir and separate out off-white solid, filter, dry to obtain prilocaine hydrochloride intermediate 181g, yield 93.0%, according to high performance liquid chromatography (HPLC ) measurement, its prilocaine hydrochloride intermediate purity 98.63%.

[0044] (b) Add 100 g of prilocaine hydrochloride intermediate to 100 g of n-propylamine solution, heat and reflu...

Embodiment 2

[0046](a) add 107g o-toluidine in 800g dichloromethane, stir at room temperature in the reaction flask of 1000ml, rotating speed is 80 revolutions per minute, drip 128.5g α-chloropropionyl chloride under the condition of room temperature, rate of addition per minute is 4.5g, the dropping time is 30min. After dropping α-chloropropionyl chloride, the reaction solution is kept at 22°C for 2 hours. Wash with 5% aqueous sodium carbonate solution, discard the upper layer, add 220g of water to the organic layer, stir and precipitate an off-white solid, filter, and dry to obtain 176g of prilocaine hydrochloride intermediate, yield: 89.06%, according to high performance liquid chromatography Method (HPLC) measures, and its prilocaine hydrochloride intermediate purity 98.72%.

[0047] (b) Add 100 g of prilocaine hydrochloride intermediate to 100 g of n-propylamine solution, heat to reflux for 7 hours, after the reaction is finished, add concentrated hydrochloric acid to adjust pH=1-2, p...

Embodiment 3

[0049] (a) Add 107g o-toluidine in 750g methylene chloride, stir at room temperature in a 1000ml reaction flask, the rotating speed is 80 revolutions per minute, drop 142g α-chloropropionyl chloride under room temperature, the rate of addition is 4.5 per minute g, the dropping time is 30min. After dropping α-chloropropionyl chloride, the reaction solution is incubated at 18°C ​​for 3 hours. After the incubation is completed, the reaction solution is washed with 5.5% hydrochloric acid, the upper layer is discarded, the organic layer is retained, and the organic layer is reused. Wash with 4% aqueous sodium carbonate solution, discard the upper layer, add 160% water to the organic layer, stir and precipitate an off-white solid, filter, and dry to obtain 179.2g of prilocaine hydrochloride intermediate, yield: 90.67%, according to high performance liquid chromatography (HPLC) measures, and its prilocaine hydrochloride intermediate purity 98.90%.

[0050] (b) Add 100g of prilocaine ...

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Abstract

The invention relates to a synthetic process of anesthetic, in particular to a method for preparing propitocaine hydrochloride. The method includes the following steps that a, ortho-toluidine is added into dichloromethane, alpha-propionyl chloride is dropwise added at the room temperature, and the reaction lasts for 2-3 h at the temperature of 15 DEG C-25 DEG C, acid solution washing is performed on the obtained reaction liquid, then, aqueous alkali washing is performed on the obtained reaction liquid, water is added to an organic layer to separate solids out, and then propitocaine hydrochloride midbody is obtained through filtration; b, the propitocaine hydrochloride midbody obtained in the step a is added into n-propylamine, reflux is heated for 5-7 h, after the reaction is ended, concentrated hydrochloric acid is added to adjust the PH to be 1-2, white solids are separated out and are refined through ethyl alcohol of 95%, and therefore the propitocaine hydrochloride is obtained. An acetone solvent which is unfriendly to the environment and has hypotoxicity in a traditional method is replaced by the commonly used solvent dichloromethane which is basically free of toxic, and therefore environment-friendly industrial mass production becomes possible on the premise of not affecting the yield.

Description

technical field [0001] The invention relates to a synthesis process of an anesthetic, in particular to a preparation method of prilocaine hydrochloride. Background technique [0002] Prilocaine hydrochloride, molecular formula: C 13 h 21 CLN 2 O, molecular weight: 256.77. [0003] [0004] Prilocaine hydrochloride is the hydrochloride salt of prilocaine, which can improve its solubility in water and the stability of solid. [0005] Use benzene or toluene as solvent in the traditional prilocaine hydrochloride preparation method, use sodium carbonate and salt of wormwood as catalyzer or synthesize with pyridine as solvent or catalyzer, because used benzene class toxicity bigger solvent and pyridine class strong Irritant substances are not conducive to large-scale industrial production, and the catalytic efficiency of sodium carbonate and potassium carbonate is not high. And because the synthesis process is not optimal, the yield is further reduced. [0006] Chinese pa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/04C07C231/12C07C231/24
Inventor 王庭见郭桂生杨彦军李跃东刘志文
Owner 山东诚汇双达药业有限公司